Bronchiolitis and Non-Cystic Fibrosis

BronchiectasisChristopher H. Fanta, M.D.

Pulmonary and Critical Care DivisionBrigham and Women’s Hospital

Partners Asthma CenterHarvard Medical School

Disclosure of Conflicts of Interest

UpToDate - AuthorSamsung Research of America – Research grant

Bronchiolitis: Definition

Acute or chronic cellular inflammation or fibrosisof the bronchiolar walls.

Acute: Viral (e.g., RSV), mycoplasmaAspiration

Chronic: Follicular bronchiolitis (C-V diseases)Mineral dust bronchiolitisCigarette smoke respiratory bronchiolitisDiffuse panbronchiolitis (Japan)Bronchiolitis obliterans

Bronchiolitis Obliterans: Etiologies• Toxic fume inhalation (e.g., nitrogen oxides in silo

filler’s lung disease; diacetyl in workers exposed to artificial butter flavoring for popcorn; vaping)

• Post-infectious (e.g., viral, mycoplasma)

• Immune-mediated• Rheumatoid arthritis (+ penicillamine)• Ulcerative colitis• Paraneoplastic pemphigus/other autoimmune blistering

diseases• S/P transplantation (e.g., lung, allogeneic bone marrow)

Bronchiolitis Obliterans: Clinical Features

• Hx: dyspnea, non-productive cough

• P.E.: inspiratory crackles; mid-inspiratory squeak; expiratory wheezes

• CXR: hyperinflation; + small patchy parenchymal infiltrates

Radiographic Findings on CT Imaging

• Centrilobular micronodules (often tree-in-bud distribution)

• Bronchiolectasis• Bronchial wall thickening• Mosaic attenuation

Winningham PJ, et al., RadioGraphics 2017;37:777–94.

Tree-in-Bud

CT Scan in Bronchiolitis

Barker AF et al. N Engl J Med 2014;370:1820-28.

Bronchiolitis Obliterans: Diagnosis

• Typically, a clinical diagnosis (without biopsy).

• Based on airflow obstruction in the appropriate setting and in the absence of alternative etiologies (such as asthma or COPD).

• Lung biopsy infrequently employed (exception = s/p lung transplantation).

Bronchiolitis Obliterans: Treatment

• Corticosteroids (systemic/inhaled); bronchodilators; O2 as needed.

• (Post-transplant: extracorporeal photopheresis; etanercept; montelukast)

• Experimental: anti-IL-1R; inhaled liposomal cyclosporine A

Bronchiolitis obliterans is often refractory to therapy.

Bronchiectasis: Definition

Irreversible airway wall damage and dilatation (-ectasis) of the bronchi, usually associated with chronic airway infection

Clinical Presentations:Historical Features

! Chronic productive cough! Recurrent hemoptysis! Recurrent focal pneumonia! Associations: sinusitis, infertility

Clinical Presentations:Physical Examination

! Focal inspiratory crackles! Low-pitched wheezing (“rhonchi”)! Clubbing

Clinical Presentations:Laboratory Data

! Purulent sputum! Typical bacterial isolates, especially

Pseudomonas! Abnormal chest radiograph / CT scan! Pulmonary function:

! variable: obstruction, restriction, mixed obstructive and restrictive patterns

Chest Radiography

! Focal non-homogeneous infiltrate with orientation of markings in direction of bronchovascular bundles

! Volume loss! “Tram lines”! Other: cyst formation; mucoid impaction

Primary Ciliary Dyskinesia(Immotile Cilia Syndrome)(Kartagener’s Syndrome)

• Bronchiectasis• Sinusitis• Situs inversus (50%)• Immotile sperm

Classic description: ultrastructural abnormality of cilia (e.g., absence of dynein arms)

Diagnostic Techniques in Primary Ciliary Dyskinesia

• Transmission electron microscopy• Videomicroscopy• Immunofluorescence labeling • Nasal exhaled nitric oxide• Genetic analysis

Chest CT Appearance

! Lack of bronchial tapering

! Bronchial dilatation (internal diameter > 1.5 x diameter of accompany vessel)

! Visualization of bronchi in lung periphery (within 1 cm of pleura)

! Bronchial wall thickening may be present

Bronchiectasis with mucoid impaction

Etiologies

! Localized! Post-pneumonic! Distal to bronchial obstruction

! Widespread! Cystic fibrosis! Primary ciliary dyskinesia ! Hypogammaglobulinemia

Etiologies:Special Syndromes

! Congenital anatomic defects! Williams-Campbell syndrome (bronchial cartilage

deficiency)! Yellow nails syndrome (lymphatic hypoplasia)! Young’s syndrome (bronchiectasis and

azospermia) ! Munier-Kuhn syndrome (tracheobronchomegaly: trachea >30 mm; right mainstem >20 mm, left mainstem >18 mm)

! Alpha-1 antitrypsin deficiency

Etiologies:Other Observations

! AIDS! Ulcerative colitis! Rheumatoid arthritis! Allergic bronchopulmonary aspergillosis! Non-tuberculous mycobacterial infection

Central bronchiectasis (ABPA)

Central bronchiectasis (ABPA)

Diagnosis of ABPA

• Asthma or cystic fibrosis• IgE (>1000 ng/ml)• Aspergillus-specific IgE (or skin test)• Aspergillus-specific IgG• Peripheral blood eosinophilia• Aspergillus isolated from sputum

MAI pulmonary infection

Tree-in-Bud: Differential Diagnosis• Infections

• Mycobacterial• Fungal (aspergillus)• Viral (CMV)• Bacterial (H. influenzae)

• Bronchiolitis obliterans• Aspiration pneumonitis• Sarcoidosis

Therefore, Dx of NTM = history, imaging, and sputum isolates X2 or bronchoscopic X1

Patient Evaluation

! Chest X-ray/CT scan! Pulmonary function/gas exchange! Sputum culture! Immunoglobulin analysis! Other: sweat chloride; genetic typing; semen

analysis; nasal or bronchial biopsy; alpha-1 antitrypsin level; IgE and aspergillus-specific IgE

! Bronchoscopy (new, local disease)

Treatment

! Predisposing condition! Gammaglobulin replacement! Systemic corticosteroids/antifungals in ABPA! (?) a1-antitrypsin replacement in AAT

deficiency! CFTR modulators

Treatment

! Bronchiectasis itselfI. Mild, intermittently symptomaticII. Persistent symptoms and morbidityIII. Acute-on-chronic exacerbations

Therapeutic Options

! Antibiotics! Mucolytics! Clearance of secretions! Bronchodilators! Anti-inflammatory Rx:

macrolide antibiotics; ? corticosteroids

Antibiotic Therapy

! Intermittent antibiotics! Chronic, rotating antibiotics! Inhaled antibiotics! Intravenous antibiotics (for refractory

infections or resistant pathogens)

Randomized Trials ofSuppressive Antibiotics

520 patients with cystic fibrosis randomized to inhaled tobramycin 300 mg BID vs. placebo every other month for 6 months.

Outcomes: Lung function (FEV1)Density of Ps. aeruginosa in sputumNeed for hospitalization/intravenous antibiotics

Ramsey BW, et al., N Engl J Med 1999; 340:23-30

Randomized Trial ofNebulized Tobramycin in CF

Change in Lung Function

Ramsey BW, et al., N Engl J Med 1999; 340:23-30

Randomized Trial of Nebulized Tobramycin in CF

Tobramycin Placebo

% of pts. hospitalized 37 45 (26% )at least once

% of pts. receiving i.v. 39 52 (36% )antibiotics at least once

Ramsey BW, et al., N Engl J Med 1999; 340:23-30

Other Inhaled Antibiotics

• Tobramycin Podhaler• Colymycin• Aztreonam

Therapeutic Options

! Mucolytics! Iodides! Guaifenesin! Acetylcysteine (Mucomyst®)! rh-DNase (Pulmozyme®)! Hyperosmolar aerosols (3%-7% NaCl)

Mucolytics:rh-DNase in “Idiopathic” Bronchiectasis

349 patients recruited from 23 centers, randomly assigned to rh-DNase or placebo twice daily for 6 months.

Outcomes: Number of exacerbationsLung function (FEV1)Quality of life

O’Donnell AE, et al., Chest 1998; 113:1329-34

rh-DNase Placebo

No. of exacerbations/pt. 0.66 0.56% change in FEV1 -3.6 -1.7 p< 0.05

Antibiotic use (days) 56.9 44.1 p< 0.05

No. of hospitalizations/pt. 0.39 0.21

Mucolytics:rh-DNase in “Idiopathic” Bronchiectasis

O’Donnell AE, et al., Chest 1998; 113:1329-34

Observations from this large-scale, prospective study of bronchiectasis (placebo group):

• Average annualized decline in FEV1 = 53 ml/yr.

• No. of pulmonary exacerbations » 1 every 8 mos.

Mucolytics:rh-DNase in “Idiopathic” Bronchiectasis

O’Donnell AE, et al., Chest 1998; 113:1329-34

Therapeutic Options

! Clearance of secretions! Chest physiotherapy and postural drainage! PEP bronchial vibrating device! External electric vibrator! Pneumatic vest! Exercise

Cough-Assist Devices

Anti-Inflammatory Therapy! Inhaled corticosteroids

! Macrolide antibiotics

• Two randomized, placebo-controlledtrials of azithromycin found fewer exacerbations over 1 year of observation compared with placebo.

Altenburg J, et al. JAMA 2013; 309:1251-9.Wong C, et al. Lancet 2012; 380:660-7.

BAT Trial

Altenburg J, et al. JAMA 2013; 309:1251-9.

Complications

! Hemoptysis, including massive hemoptysis! Infection with resistant organisms! Hypercapnic respiratory failure! Other: weight loss, mycetoma

Bronchiolitis: Key Points

• Bronchiolitis is a mixed group of disorders, both acute and chronic, involving respiratory bronchioles.

• Etiologies include infection, toxic exposures, and underlying immune disorders.

Bronchiolitis: Key Points

• Imaging varies considerably and is often non-specific.

• Biopsies are infrequently performed, leading to clinical diagnosis based on exclusion of other disorders.

• Treatment generally involves corticosteroids and other immunosuppression.

Key Points

! Bronchiectasis is a structural abnormality of the airways that predisposes to chronic airway infection.

! Symptoms may be intermittent or daily and include productive cough and periodic hemoptysis.

Key Points

! Etiologies include structural, immunologic, rheologic, and infectious causes.

! Chest CT scan is both sensitive and specific for diagnosis.

! Sputum culture is useful to guide treatment.

Key Points

! Treatment focuses on antibiotic treatment and airway clearance.

! Chronic suppressive antibiotics are effective but pose risk for emergence of resistant organisms.

Multiple-Choice Question:48-year-old cigarette smoker with productive cough.

Multiple-Choice Question:Close-Up of left base

Question:

Which of the following blood tests is most likely to be helpful in assessment of this patient?

A. Cystic fibrosis gene mutationB. ANCAC. Alpha-1 antitrypsin levelD. VEGF-DE. Serum immunoglobulin E

Correct Answer:

Which of the following blood tests is most likely to be helpful in assessment of this patient?

A. Cystic fibrosis gene mutationB. ANCAC. Alpha-1 antitrypsin levelD. VEGF-DE. Serum immunoglobulin E

References• Brodt AM, et al. Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis. Eur Resp J 2014; 44:382-93.• McShane PJ, et al. Non-cystic fibrosis bronchiectasis.

AJRCCM 2013; 188;647-56.• Pulverino E, et al., European Respiratory Society

guidelines for the management of adult bronchiectasis. Eur Resp J 2017; 50: 1700629.

• Barker AF, et al. Obliterative bronchiolitis. NEJM2014; 370:1820-28.

• Ryu JH, et al. Bronchiolar disorders. AJRCCM 2003; 168:1277-92.